Enalapril is an ACE inhibitor useful in treating hypertension and heart failure. It is currently marketed in the United States under the trademark VASOTEC (enalapril maleate). It is disclosed and claimed in U.S. Pat. No. 4,374,829.
U.S. Pat. Nos. 4,374,829, 4,472,380 and 4,510,083 disclose methods useful in the preparation of enalapril. The large-scale synthesis of enalapril (1) involves a key diastereoselective reductive amination reaction between the .alpha.-ketoester (2) and the dipeptide, alanylproline (3), catalyzed by Raney-Nickel (Ra-Ni). [Blacklock, T. J.; Shuman, R. F.; Butcher, J. W.; Shearin, W. E. Jr.; Budavari, J.; Grenda, V. J.; J. Org. Chem. 1988, 53, 836-844.] The initially reported conditions gave a diastereomer ratio of 6.7:1. Over the past decade, this ratio has been improved to 11:1 using traditional optimization techniques, primarily with the Ra-Ni catalyst. The best ratio achieved with a catalyst other than Ra-Ni was 1.5:1 using palladium on carbon or IrO.sub.2. ##STR1##